Abstract 2271: Development and characterization of SL-115154 (CSF1R-Fc-CD40L) for cancer immunotherapy
Authors: Taylor H. Schreiber, George Fromm, Suresh De Silva, Arpita Patel, Kellsey Johannes, Kyung Jin Yoo, Kaiwen Huang
Journal: Cancer Research (2019)

Abstract SL-115154 (CSF1R-Fc-CD40L) is a first-in-class biologic derived from the Agonist Redirected Checkpoint (ARC™) platform developed by Shattuck Labs. The ARC platform was developed to solve a fundamental challenge in cancer immunotherapy, which was to develop combination therapeutics that could block immune checkpoints (such as PD-1), while simultaneously activating Tumor Necrosis Factor (TNF) SuperFamily Receptors (such as OX40, 4-1BB, GITR and CD40). Pre-clinical development of SL-115154 has been completed, and demonstrated that the CD40L end of the ARC binds immobilized CD40 at 0.8 nM affinity and was found to saturate physiological levels of soluble CSF1 at molar ratios of approximate 1 CSF1 to 2-3 ARC molecules; levels which are easily achievable in the clinic. CSF1R-Fc-CD40L binds CD40 on plate bound recombinant receptors and on cells, and in NHP tox immunophenotyping studies, was found to deplete specific populations of CD20+ B cells. Sequestrations of CSF1 and depletion of B cells demonstrated on-target activity culminating in the secretion of cytokines specific to this ARC; including IL-7 &amp; IL-15. SL-115154 was also shown to be highly potent in a series of in potency assays including: CD40 dependent NFkB reporter assays, TCR-independent proliferation/cytokine ELISpot assays, and TCR-dependent SEB super antigen cytokine release assays. In addition, the anti-tumor efficacy of the mouse surrogate CSF1R-Fc-CD40L, was superior to monotherapy or combination treatment with anti-CSF1R and anti-CD40 antibodies and lacked any evidence of toxicity observed with the antibody combination. Interestingly, anti-tumor activity and the rejection of primary and ‘re-challenged’ secondary tumors, was significantly enhanced when CSF1R-Fc-CD40L was sequenced with or following anti-CTLA4 or anti-PD1 therapy. A PD1-resistant in vivo model was established in the mouse to examine CSF1R-Fc-CD40L mono- and combo- efficacy in the molecular context to which most available patients will belong during the phase I study. These data demonstrate feasibility and functional activity of a novel chimeric fusion protein platform, providing cytokine sequestration of CSF1 by CSF1R, along with APC co-stimulation via the CD40/L axis. This strategy may uniquely inhibit immunosuppressive signaling / DC differentiation into pro inflammatory phenotypes, and instead promote an M1 phenotype and co-stimulation of CD40 positive cells, increasing cell activation, antigen presentation/processing, and enhanced anti-tumor response. Citation Format: Taylor H. Schreiber, George Fromm, Suresh De Silva, Arpita Patel, Kellsey Johannes, Kyung Jin Yoo, Kaiwen Huang. Development and characterization of SL-115154 (CSF1R-Fc-CD40L) for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2271.